Amino ethers



Patented Oct. 31, 1950 AMINO ETHERS George Rieveschl, Jia, Grosse PointeWoods, Mich, assignor to Parke, Davis & Company, Detroit, Mich, acorporation of Michigan No Drawing. Application October 15, 1947, SerialNo. 780,099

4 Claims. (01. 26(l570) This invention relates to a substitutedfi-dialkylaminoalkyl benzhydryl ether and its salts and to methods forobtaining the same. More particularly, the invention relates to6-dimethylaminoethyl p-methylbenzhydryl ether and its salts. The freebase of the amino ether of this invention has the formula,

CH3 CH-O- CHzCHzN c Dimethylaminoethyl p methylbenzhydryl ether can beprepared by several different processes. For example, it may be preparedby the condensation of a p-methylbenzhydryl halide withfi-dimethylaminoethanol. The condensa-.

tion of these two reactants may be carried out by several differentmethods, e. g., it may be effected in the presence or absence of an acidbinding agent or with or without a solvent. Another method for preparingthis compound consists in reacting an alkali metal salt ofp-methylbenzhydrol with a fl-dimethylaminoethyl halide or, if desired,the reactants may be interchanged and an alkali metal salt of,B-dimethylaminoethanol reacted with a p-methylbenzhydryl halide. Afurther method of preparation consists in reacting a fi-haloethylp-methylbenzhydryl ether with dimethylamine.

The free base and the acid addition salts of fl-dimethylaminoethylp-methylbenzhydryl ether are powerful anti-histamine agent. They arealso useful in preventing smooth muscle spasms induced by histamine,acetyl choline or barium chloride. is that they inhibit gastricsecretion which has been induced either by meal or histamine stimulus.These new products may be administered to humans orally, parenterally,rectally or as a vapor or mist. They find particular us in humans forthe treatment of allergic conditions (asthma,

Another property of these compounds The invention is illustrated by thefollowing example.

Example 25 cc. of acetyl bromide is added slowly with stirring 39.7 g.of p-methylbenzhydrol dissolved in 100 cc. of benzene. After theaddition has been completed the reaction mixture is refluxed for aboutthree hours and then the benzene, excess acetyl bromide and the aceticacid which is formed distilled off under reduced pressures to obtain thedesired p-methylbenzhydryl bromide.

The p-methylbenzhydryl bromide prepared above is dissolved in 25 cc. ofxylene and the solution added slowly to a refluxing solution consistingof 40 cc. of fl-dimethylaminoethanol in 50 cc. of xylene. After theaddition has been completed the reaction mixture is refluxed for abouttwo hours, cooled and treated with aboutlOO cc. of water. The layers areseparated, the aqueous layer extracted once with ether'and thendiscarded. The ether extract is combined with the organic layer, thecombined extract washed with water and then extracted with severalportions of 2 N hydrochloric acid (total volume about 200 Co). Theacidic extract is clarified by extracting with ether once, the etherdiscarded and the urticaria, histamine cephalagia and anaphylacticaqueous solution made alkaline with 40 or 50% sodium hydroxide solution.The free base of the fl-dimethylaminoethyl p-methylbenzhydryl etherwhich separates is extracted from the aqueous solution with about 400cc. of ether, the ether extracts washed with water and then dried overanhydrous potassium carbonate. The drying agent is removed by filtrationand the filtrate made acidic to Congo red by the addition of anisopropanol solution of dry hydrogen chloride. The hydrochloride salt offi-dimethylaminoethyl p-methylbenzhydryl ether which separates iscollected, washed with ether and dried in vacuo; yield about 50 g. Thissalt which has the formula,

after purification by recrystallization from isopropanol-anhydrous ethermixture melts at 143.5 to 145.5 C.

If desired, the B-dimethylaminoethyl p-methylbenzhydryl ether may beisolated from the above reaction mixture as the free base rather than asthe hydrochloride salt. This is accomplished by evaporating the etherfrom the dry ether extract containing the crude free base offl-dimethylaminoethyl p-methylbenzhydryl ether and distilling theresidue under reduced pressure (about 3 to 5 mm. of Hg). Thefi-dimethylaminoethyl p-methylbenzhydryl ether free base thus obtainedis a light yellow to colorless oily liquid.

The acid addition salts of p-dimethylaminoethyl p-methylbenzhydryl ethercan be prepared either from the crude free base, as illustrated above inthe case of the hydrochloride salt, or from the purified free base. Whenstarting with the purified free base, one dissolves it in an alcohol,ether or benzene or the like and then adds the solution to, or to thesolution, the acid corresponding to the desired salt. For example, theoxalate salt may be prepared as follows:

g. of free base of p-dimethylaminoethyl pmethylbenzhydrylether isdissolved in a small amount of isopropanol and the resulting solutionadded with stirring to a Warm isopropanol solution containing oneequivalent of oxalic acid monohydrate. The white, crystalline acidoxalate salt of e-dimethylaminoethyl p-methylbenzhydryl ether whichseparates on cooling is collected and purified by recrystallization fromisopropanol.

The hydrobromide salt can be prepared by dissolving 10 g. of the freebase of fl-dimethylaminoethyl p-methylbenzhydryl ether in anhydrousether and treating the solution with an excess of dry gaseous hydrogenbromide. The White hydrobromide salt of p-dimethylaminoethylp-methylbenzhydryl ether which separates from the solution is collectedand purified by recrystallization from isopropanol anhydrous ethermixture.

In its broader aspects the invention includes the quaternary ammonium,as well as the" acid addition, salts of fl-dimethylaminoethylp-methylbenzhydryl ether. These quaternary ammonium salts are preparedby reacting an alkyl or aralkyl halide, a dialkyl sulfate or an alkylaryl sulfonate with the free base of s-dimethylaminoethylp-methylbenzhydryl ether. The quaternary ammonium halides can also beprepared by the reaction of a fi-haloethyl p-methylbenzhydryl ether witha dimethyl-a1kyl-amine. Some specific examples of the quaternaryammonium salts which can be prepared by the foregoing methods are themethochloride, methobromide, methiodide, methosulfate, methyl ptoluenesulfonate and the benzyl chloride salts.

What I claim as my invention is:

1. A compound of the class consisting of a free base, and its acidaddition salts, said free base having the formula,

2. p-Dimethylaminoethyl p-methylbenzhydryl ether.

3. An acid addition salt of fl-dimethylaminoethyl p-methylbenzhydrylether.

4. ,B-Dimethylaminoethyl p-methylbenzhydryl ether hydrochloride.

GEORGE REVESCHL, JR.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 2,397,799 Martin et al. Apr. 2,1946 2,421,714 Rieveschl -1 June 3, 1947 2,464,260 Rieveschl Mar. 15,1949 OTHER REFERENCES Loew et al., Proc. Soc. E'xpt. Biol. and Med,

vol. 58, March, 1945, pp. 235 to 237.

Winder et al., J. Pharmacol, vol. 87 (1946), pp. 124 and 125.

1. A COMPOUND OF THE CLASS CONSISTING OF A FREE BASE, AND ITS ACIDADDITION SALTS, SAID FREE BASE HAVING THE FORMULA,